Abstract

Background

Lithium is considered by many as the gold standard medication in the management of
bipolar disorder (BD). However, the clinical response to lithium is heterogeneous,
and the molecular basis for this difference in response is unknown. In the present
study, we sought to determine how the peripheral blood gene expression profiles of
patients with bipolar disorder (BD) changed over time following intitiation of treatment
with lithium, and whether differences in those profiles over time were related to
the clinical response.

Methods

Illumina Sentrix Beadchip (Human-6v2) microarrays containing > 48,000 transcript probes
were used to measure levels of expression of gene-expression in peripheral blood from
20 depressed subjects with BD prior to and every two weeks during 8 weeks of open-label
treatment with lithium.

Changes in gene-expression were compared between treatment responders (defined as
a decrease in the Hamilton Depression Rating Scale of 50% or more) and non-responders.
Pathway analysis was conducted using GeneGO Metacore software.

Results

127 genes showed a differential response in responders vs. non-responders. Pathway
analysis showed that regulation of apoptosis was the most significantly affected pathway
among these genes. Closer examination of the time-course of changes among BCL2 related
genes showed that in lithium-responders, one month after starting treatment with lithium,
several anti-apoptotic genes including Bcl2 and insulin receptor substrate 2 (IRS2)
were up-regulated, while pro-apoptotic genes, including BCL2-antagonist/killer 1 (BAK1)
and BCL2-associated agonist of cell death (BAD), were down-regulated. In contrast,
in lithium non-responders, BCL2 and IRS2 were down-regulated, while BAK1 and BAD up-regulated
at the one-month time-point.

Conclusions

These results suggest that differential changes in the balance of pro- and anti- apoptotic
gene-expression following treatment with lithium may explain some of the heterogeneity
in clinical response in BD patients.